This is a revised application in response to PA-10-088, "Exploratory Cancer Prevention Studies Involving Molecular Targets for Bioactive Food Components (R21)". In this project, we will characterize a novel molecular target of resveratrol for colorectal cancer prevention. Colorectal cancer is the second leading cause of cancer-related mortality in the United States and accounts for more than 56,000 deaths per year. Colorectal cancer is initiated by mutations of adenomatous polyposis coli (APC) and 2-catenin genes, which result in abnormal activation of Wnt signaling. Inhibition Wnt signaling is essential for colorectal cancer chemoprevention. Resveratrol is found in the skin of red grape and also present in the red wine. Resveratrol and many of its analogs have anti-cancer activity. We found several resveratrol analogs, including pterostilbene found in blueberry, can strongly inhibit Wnt signaling, while cis-resveratrol cannot. We have designed and synthesized a panel of novel resveratrol analogs and have identified several novel inhibitors for Wnt/2-catenin signaling. Our central hypothesis is that resveratrol and its analogs inhibit Wnt signaling, thus prevent of 2-catenin-induced cancers, particularly colorectal cancers. To further understand the molecular mechanisms of resveratrol in Wnt/2-catenin inhibition and to develop better inhibitors for chemoprevention, we will pursue the following two specific aims: 1) to delineate the mechanisms of how resveratrol inhibits Wnt signaling using cell models;and 2) to investigate how resveratrol and its analogs inhibits Wnt signaling using a novel inflammation-related mouse colon cancer model. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer death in the United States. This project is to explore a novel mechanism of cancer prevention by resveratrol, a product from red grapes. We found that resveratrol blocks Wnt signaling, a key pathway in colon cancer formation. The studies in this project will provide a better understanding of resveratrol function in cancer prevention and will lead to better chemoprevention agents in the future.